1. Field of the Invention
The present invention relates to novel heterocyclic carboxylic acid ester derivatives having a serine protease (particularly trypsin and enteropeptidase) inhibitory activity. The present invention also relates to pharmaceutical compositions which contain such a heterocyclic carboxylic acid ester derivative and drugs for the prophylaxis or treatment of diabetes.
2. Discussion of the Background
At present, insulin secretagogues (sulfonylureas), glucose absorption inhibitors (α-glucosidase inhibitors), insulin sensitizers (biguanide, thiazolidine derivatives), and the like are clinically used as therapeutic drugs for diabetes. However, since all of them are accompanied by side effects such as hypoglycemia, diarrhea, lactic acidosis, edema, and the like, show an insufficient effect, and the like, a medicament satisfying clinical needs is still demanded.
In recent years, a benzoic acid ester having a protease inhibitory activity, which is represented by the following compound, has been reported to show a blood glucose elevation suppressing action in diabetes animal model (patent document 1). The following compound is considered to show an enzyme inhibitory activity on trypsin, thrombin, pancreatic, and plasma kallikreins, plasmin and the like and a leukotriene receptor antagonistic action. Moreover, an enteropeptidase inhibitory activity of the following compound has also been reported (non-patent document 1). However, many unclear points remain in the relationship between such actions and a blood glucose elevation suppressing action.

On the other hand, as for a heterocyclic carboxylic acid ester structure, patent document 2 discloses a compound as a therapeutic drug for pancreatitis. In this document, only heterocyclic carboxylic acid ester compounds wherein the substituent of the heterocyclic carboxylic acid moiety is a methyl group or a methoxy group or unsubstituted compounds are disclosed, as represented by the following formula. While these compounds are disclosed as showing an inhibitory activity on trypsin, chymotrypsin and thrombin, no description is given as to the enteropeptidase inhibitory activity and blood glucose elevation suppressing action.

In addition, non-patent document 2 also describes a heterocyclic carboxylic acid ester having a protease inhibitory activity, which is represented by the following formula. However, only compounds wherein the heterocyclic moiety is unsubstituted are disclosed, and no description is given as to the enteropeptidase inhibitory activity and blood glucose elevation suppressing action of these compounds.

Furthermore, patent document 3 describes a compound represented by the following formula. However, it has a structure wherein an aryl group is directly bonded to the heterocyclic moiety, which is completely different from the compound of the present invention. The document discloses an inhibitory activity against blood coagulation factor VIIa; however, no description is given as to the enteropeptidase inhibitory activity and blood glucose elevation suppressing action.

On the other hand, trypsin is one of the intestinal serine proteases and is produced by degradation of inactive trypsinogen by enteropeptidase. Trypsin is known to activate various digestive enzymes by acting on chymotrypsinogen, proelastase, procarboxylesterase, procolipase and pro-sucrase-isomaltase, and the like. Therefore, it is considered that an inhibitor of enteropeptidase and trypsin lowers the digestive capacity for protein, lipid, and carbohydrates, and is effective as a drug for the prophylaxis or treatment of obesity and hyperlipidemia.
Patent document 4 describes that a medicament that inhibits both enteropeptidase and trypsin is interesting as a body fat-reducing agent. In addition, patent document 5 reports a compound having an inhibitory activity against enteropeptidase, trypsin, plasmin, kallikrein, and the like as an antiobesity drug. However, neither of these publications describe suppression of blood glucose elevation and hypoglycemic effect afforded by simultaneous inhibition of enteropeptidase and trypsin, and the protease inhibitor described therein has a structure completely different from that of the compound of the present invention.